Page 654 - Hematology_ Basic Principles and Practice ( PDFDrive )

556 Part V Red Blood Cells

191
iron overload; however, it also promotes elimination of excess iron in serum ferritin levels (<1000 mg/mL). Deferoxamine chelation
patients if started after significant transfusional iron burden has regimens are clearly cumbersome, inconvenient, and costly. More
already developed. 134,157–166 Moreover, deferoxamine may adversely tolerable approaches are required, and investigations for alternative
affect bone development and growth in some young patients and the oral iron-chelating agents have been ongoing and recently more
effect of newer oral chelators on growth has yet to be addressed. 167–169 successful.
The most common side effect of subcutaneous deferoxamine therapy Although the prevalence of endocrine disturbances, for example,
is inflammation and induration at the site of infusion. Painful lumps glucose intolerance and diabetes have reduced since the regular use
may occur despite rotation of infusion sites, appropriate dilution of of subcutaneous deferoxamine, 97,100,180 they persist, especially in those
161
the drug, and proper placement of the needle. Some investigators in whom deferoxamine was initiated late in their first decade of life.
have recommended the addition of small amounts of hydrocortisone Growth hormone deficiency, hypothyroidism, hypoparathyroidism,
to the infusion to prevent local reactions. Patients receiving aggressive vitamin D deficiency, diabetes, and osteoporosis are still observed,
chelation therapy with lower iron burdens may be more susceptible and there is little evidence that deferoxamine can reverse established
to toxicity. Neurosensory toxicity of deferoxamine is dose related and endocrine dysfunctions. The North American Thalassemia Clinical
inversely correlated with body iron burden. Impairments of visual Research Network Registry reported that 96% of thalassemia patients
and auditory acuity are associated with high doses of deferoxamine with a median age of 20 years were free of hypoparathyroidism, 91%
170
relative to the iron load. The ototoxicity is characterized by bilateral were free of thyroid disease, 90% were free of diabetes mellitus, and
high-frequency hearing loss. The retinal toxicity is characterized by overall 62% were free of any endocrinopathy. 192
the loss of night and color vision, retinal atrophy, and cataract forma- It remains to be determined if starting chelation at a very young
171
tion. Patients receiving deferoxamine should undergo baseline and age or more easily administered use of oral iron chelation will dimin-
annual audiograms and ophthalmologic examinations. Deferoxamine ish the endocrine morbidities and further prolong survival associated
should be discontinued if such abnormalities arise, with cautious with iron overload. Direct and indirect measures of iron stores reflect
reinitiation at lower doses when abnormalities improve or resolve. the progress of chelation therapy and help determine appropriate
The risk of visual and auditory side effects can be minimized by changes in the dose or frequency of chelator use. The serum ferritin
adjusting the daily deferoxamine dose to the patients’ serum ferritin level generally declines during regular chelation therapy and may
170
level. Impaired growth associated with growth plate deformities or decline rapidly in the first year of treatment in patients with very large
metaphyseal rickets-like changes in the long bones and histologic iron stores. 193,194 Serum ferritin levels measured over time with use of
evidence of cartilage dysplasia may occur in young children receiving deferoxamine have predicted the risk of iron-induced heart disease in
deferoxamine. 167–169 Regular monitoring with plain radiographs of the patients with thalassemia major, and the ratio of the dose of deferox-
extremities and vertebral column allows early detection of this com- amine to the ferritin level has identified patients at risk for auditory
plication and reduction in the dose of deferoxamine or temporary and visual complications of chelation therapy. 170,183 Although easy to
interruption of chelation therapy. obtain and relatively inexpensive, the serum ferritin level may be
Other, less common complications of deferoxamine include ana- increased in the presence of inflammation and may be decreased
195
phylaxis, hypotension, allergic reactions, acute pulmonary disease, when iron overload is accompanied by vitamin C deficiency. For
impairment of renal function, and infection. 172–178 Severe allergic these and other reasons, serum ferritin levels frequently correlate
reactions are rare, and desensitization has been achieved successfully poorly with LICs, and clinicians and patients may have a false sense
in some patients. 174,175 Acute pulmonary disease and renal failure have of security when the ferritin level is below 2000 mcg/L. Some studies
occurred in a few patients receiving unusually high doses of deferox- using deferoxamine suggest ferritin levels lower than 1000 mcg/L are
176
amine by intravenous infusion. The mechanism of this toxicity is associated with better survival times and less cardiac disease as well
unclear. One of the most serious complications of deferoxamine is an as hepatic histology and pathology. 191,196,197
increased risk of infection with Yersinia and mucormycosis, which A relationship between iron overload and ascorbic acid depletion,
uses the deferoxamine iron chelate as a siderophore. Deferoxamine first suggested by the epidemiology of scurvy among the Bantu, exists
can enhance the growth and virulence of these organisms, leading to in thalassemia major. 87,195 For thalassemia patients with low levels of
colitis, abdominal abscesses, or sepsis. 177,178 The safety of deferox- ascorbic acid, daily supplementation with 100–200 mg of this
amine during pregnancy has been inferred from case reports rather vitamin increases urinary iron excretion in response to deferoxamine
than formal studies. A summary of these case reports identified 11 by approximately twofold. 88,198 Ascorbic acid may retard the conver-
women who received deferoxamine beginning in the first trimester sion of ferritin to hemosiderin and therefore allow more iron to
and 33 women who used the chelator beginning in the second or remain in the chelatable form. 199,200 However, it can also enhance
178
third trimester. None of the infants showed evidence of drug- iron-mediated peroxidation of membrane lipids 201,202 as well as
203
related toxicity. 179 membrane damage in cultured myocardial cells. Cardiac toxicity
Regular chelation with deferoxamine has proven remarkably effec- manifested as arrhythmias and decreased ventricular contractility has
204
tive in reducing the transfusional iron burden of thalassemia patients. been attributed to vitamin C therapy. Ascorbic acid should be used
Increasing evidence indicates that endocrine dysfunction is improved only while deferoxamine is being administered and only in patients
and cardiac disease is delayed or prevented with standard deferox- who are ascorbate depleted.
180
amine regimens. Cardiac arrhythmias and congestive heart failure Chelation therapy with deferoxamine is expensive and cumber-
have reversed in some patients with standard or aggressive deferox- some because of the need for daily or nightly subcutaneous infusions.
amine regimens, and life expectancy is significantly prolonged. 181–183 Regular infusions require a great deal of dedication and persistence
Intense 24-hour intravenous deferoxamine regimens of no more than from the patient and family. Noncompliance is common, particularly
15 mg/kg/h have been reported to reverse early cardiac hemosiderosis, in the teenage and young adult years, and failure to follow prescribed
but even more conventional doses of 50 mg/kg/d have improved treatment regimens is the major cause of mortality in patients with
191
left ventricular ejection fractions and prevented death in some thalassemia major. The cost and complexity of deferoxamine
patients. 184,185 administration prevents its availability worldwide, especially in
Before subcutaneous deferoxamine therapy, estimated survival was developing countries. The search for a less expensive iron chelator
approximately 16 to 17 years of age, with rare patients surviving that can be more easily orally administered led to the identification
into their mid-20s. 104,182,186,187 Since regular subcutaneous defer- of compounds such as deferiprone and deferasirox.
oxamine regimens have been in use, life expectancy has extended
into the fourth decade of life. 188–190 The increasing widespread use
of deferoxamine has steadily increased survival probabilities world- Deferiprone
wide. 189,190 However, long-term European studies have demonstrated
that improved survival times are clearly related to the degree of One such oral agent is 1,2-dimethyl-3-hydroxypyrid-4-one (L1,
compliance with chelation regimens and are associated with lower deferiprone), a synthetic compound with a low molecular weight of